Experimental autoimmune encephalomyelitis (EAE) serves as a model for human multiple sclerosis (MS). Both EAE and MS manifest as a consequence of an inflammatory process within the central nervous system (CNS) that is mediated by cells of the immune system. The disease develops when T regulatory cells (Tregs) are no longer able to control activation of myelin-reactive effector T cells. It is thus crucial to understand why Tregs become unable to keep effector T cells in check and how the myelin-reactive lymphocytes evade such control in order to develop approaches that could contain the disease. Recently, we discovered a novel class of thymic stem cell progenitors expressing IL-13 receptor 1 (IL-13R1) that contribute to the development and function of both Tregs and effector T cells. The lineage negative (Lin-) IL-13R1+ stem cells, which arise in the bone marrow (BM), migrate to the thymus and become early thymic progenitors (ETPs). However, these IL-13R1+ ETPs do not mature into T lymphocytes. Rather, they give rise to CD11b+ myeloid cells that are retained in the thymus and function as antigen-presenting cells (APCs) that contribute to the selection process of both Tregs and effector T cells. The IL-13R1+ BM stem cells that do not migrate to the thymus also give rise to IL-13R1+ myeloid cells as well as dendritic cells (DCs) that likely function as peripheral APCs and contribute to the function of Tregs and effector T cells. The long term objective in this proposal is to define the contribution of IL-13R1+ ETPs to thymic T cell selection and to determine how the IL-13R1+ BM stem cell-derived peripheral APCs (myeloid and DCs) regulate the function of the ETP-selected Tregs and effector T cells. The major hypothesis in this proposal postulates that IL-13R1+ETP-derived myeloid cells function as APCs for thymic selection and display discrepancies among effector and regulatory T cells as well as self versus foreign antigens. Ultimately, the thymic outcome dictates T cell output to the periphery and, in coordination with the IL- 13R1+ peripheral APCs, regulates myelin-reactivity and EAE. Three aims are proposed to test these hypotheses. Aim 1 will define the role IL-13R1+ETPs play in thymic T cell selection, aim 2 will assess the role IL-13R1+ ETPs play in the development of peripheral T cell responses and EAE, and aim 3 will determine how IL-13R1+ Lin- BM stem cells regulate T cell responses and EAE. This study is of high impact because it could yield mechanistic insights useful for the generation of therapeutics against EAE and MS.